Positron-Emission Particle Tracking Could Demystify Mixing

Is pharmaceutical manufacturing as much an art as a science? Consider this: pharmaceutical companies produce the majority of their drugs as tablets or capsules. But despite the industry’s long experience with creating these dosage forms from powdered ingredients, many aspects of powder behavior and blending operations remain mysterious. Regulatory initiatives and the need for efficiency are pressing drugmakers to gain a better understanding of their processes. Positron-emission particle tracking (PEPT), a new technique developed by David Parker, professor of physics at the United Kingdom’s University of Birmingham, could shed light on flow processes. Equipment & Processing Report talked to Parker’s colleague Jonathan Seville, dean of the School of Engineering at the University of Warwick, to find out more about the technique.

EPR: How does PEPT work?

Seville: In PEPT, we make a single particle into a positron emitter and follow it around in a process. We normally use fluorine 18 as the radioactive material, which is made from oxygen in a cyclotron. We produce radioactive water—positron-emitting water—and attach it to the surface of a particle. We aim to put into the process a particle with properties identical to those of the bulk. When positrons are produced, they annihilate with electrons to produce two gamma rays that travel along the same line in opposite directions. We track the particle during the process by triangulation.

EPR: What kind of equipment does PEPT require?

Seville: We started with a conventional positron-emission tomography scanner. In the past 10 years, we’ve acquired redundant medical scanners from hospitals, broken them down into their detectors, and built the detectors back up into boxes that we can set around the equipment we’re interested in. That’s reasonably easy to do, and you get something that is optimized for that geometry.

EPR:How do you analyze a mixing process with PEPT?

Seville: Add a radioactive particle, currently the lower size limit is about 60μm, and follow its motions for as long as an hour. It will show whether the material is visiting all parts of the mixer. It results in a plot of the dispersion associated with each volume element of the mixer. That plot shows where the mixing is going on.

EPR: What are the advantages of PEPT?

Seville: Gamma rays are penetrating. They let operators see through metal walls 1 cm thick, so they can look at real pieces of equipment. In particle-tracking mode, scientists find the particle by triangulation, and that’s very fast and produces lots of data. The particle can be found at least 100 times per second. The technique can reveal particle velocities as high as 10 m/s without too much difficulty. That’s much better than other radioactive tracking techniques could normally achieve. The other big advantage, from my point of view, is that it’s quite easy to attach a positron emitter to a lot of things. Also, operators don’t have to stop the mixer because PEPT is a fast technique. It’s almost a real-time technique.

EPR: Does the technique have drawbacks?

Seville: The need for the equipment is a drawback. Several pharmaceutical companies probably do have PET cameras, but they can’t do this technique simply with a PET camera. Although the hardware is the same, the software is completely different. Also, the amount of radioactivity involved is tiny, but most industries are extremely nervous about using radioactivity in a production environment.

EPR: How could PEPT improve pharmaceutical manufacturing processes?

Seville: It’s a background technique rather than something you would use on your production line. I think it would certainly tell you the best place on your vessel to put your near-infrared sensor to get a typical result.

EPR: Could PEPT be used for process development?

Seville: Yes. People use it to understand physical processes such as mixing. In my experience, it provides information that you simply can’t get from any other technique.

Operators also could use PEPT to scale a process up to an intermediate size. It depends on how big the production scale is. Many pharmaceutical processes are of a reasonable scale that we could look at. At a smaller scale, we can give people a complete visual image of the motion everywhere in the vessel. As the scale gets bigger, we might find it rather difficult to give a complete picture. We might end up giving cycle-time information, but I think that’s nevertheless useful.

EPR: Have you used the technique in any joint projects with pharmaceutical companies?

Seville: We’ve done work with pharmaceutical companies on coating. We’ve taken a single pellet or tablet, made that into a positron emitter, followed it around a Wurster coater, and looked to see where it comes into the spray region and where it goes out of the spray region. Colleagues at Birmingham and I also have done work on coating for Merck, Sharp, and Dohme [Whitehouse Station, NJ]. And we’ve done work on mixing and granulation for GlaxoSmithKline [London] and on fluidization and flow for many companies.